The TNF-family cytokine BAFF is a produced by a number of cell types including dendritic cells (DCs), lymphocytes and stromal cells. BAFF is essential for mature B cells to develop and to respond to antigens (Ags). Dysregulation of BAFF contributes to autoimmune diseases like systemic lupus erythematosus (SLE) and to B cell malignancies. Little is known about when, where and how BAFF is produced in vivo and about which BAFF- producing cells contribute to B cell maturation, B cell responses and B cell-associated diseases. We will address this by using two novel transgenic (Tg) mouse lines we have developed: BAFF reporter (BAFF.TRT) and BAFF floxed (BAFFfl/fl) mice. We will define how tissue and cell specific expression of BAFF is regulated and determine which BAFF- producing cells contribute to immune responses and B cell-associated autoimmune disease. In Aim 1 will use BAFF.TRT reporter mice to determine which cells upregulate BAFF after exposure to Ags or Salmonella typhimurium that induce extrafollicular (EF) antibody (Ab) responses. Using BAFFfl/fl mice crossed to Cre recombinase lines that are missing BAFF in dendritic cells (DCs), macrophages and/or neutrophils, we will define which cells must produce BAFF for EF responses to develop. In Aim 2 will use BAFF.TRT reporter mice to determine which cells upregulate BAFF after exposure to Ags or Salmonella typhimurium that induce germinal center (GC) formation, memory B cell and long lived plasma cells. We will investigate the role of myeloid-, T cell- and follicular dendritic cell-derived BAFF in these humoral immune responses. In Aim 3 we will define how BAFF is regulated during the development of autoimmune disease and the sources of BAFF required for the development of autoAbs and disease. We will cross B6.BAFF.TRT reporter and certain B6.BAFFfl/fl conditional knockout mice to B6.Sle1 and B6.TLR7 transgenic mice that develop lupus-like autoimmunity to define how dysregulated TLR7 affects BAFF expression and BAFF-dependent autoimmune disease. These studies will impact our understanding of and how best to vaccinate to generate long-lived humoral immunity and how to treat BAFF-driven disease processes.